Rotaviruses, members of the family Reoviridae, are the most important cause of severe acute diarrhea in infants and young children and on an annual basis are responsible for nearly one million deaths worldwide. Their medical significance has stimulated extensive and successful efforts towards the development of rotavirus vaccines by the Laboratory of Infectious Diseases (LID) at the NIH. Specifically, a rotavirus tetravalent vaccine developed by the LID has been shown in large scale phase III trials to have an efficacy of protection against severe and life-threatening dehydrating diarrhea of approximately 90%. The vaccine is somewhat less effective against preventing instances of mild and moderate diarrhea stemming from rotavirus infection. The overall goal of this project is to identify loci within the rotavirus genome that affect the antigenicity and virulence of the virus and then to use this information in combination with a reverse genetics system to improve and modify existing live virus vaccines and to develop second generation vaccines. An important secondary goal of the project includes exploring the potential usefulness of rotavirus as vectors for immunization against other enteric pathogens.